Eicosanoids -- Prostaglandins, Leukotrienes, and Thromboxanes -- (PGs, LTs, TXs) -- These agents are synthesised from cell wall components as illustrated below and released in response to a variety of stimuli, including direct cellular injury, immune system mediated factors, and receptor occupation by various neurotransmitters and/or autocoids.

NOTE that cyclooxygenase I (COX I) is continuously present and its activity may increase 2- to 4-fold in response to certain situations.  It is thought that this continued presence is primarily responsible for normal cytoprotective effects of prostaglandins on the gastric mucosa and for normal platelet aggregation functions of the TXs.  Cyclooxygenase II (COX II) is thought to be primarily responsible for pain and inflammatory responses.  It is expressed upon exposure to cytokines, growth factors, and endotoxin.  The presence of these stimuli will increase levels of COX II 10-fold.   NOTE also, that the expression of COX II is DECREASED by cortisol.

The eicosanoids exert their effect by interacting with specific G-coupled proteins.  The effector mechanisms are receptor specific and may be G_s, G_i/o, or G_q/11 mediated.

Effects of the Eicosanoids
Heart -- LTC₄ and LTD₄ -- negative inotropic effects and smooth muscle cell attractants in response to injury.

Smooth Muscle --

Vascular --
TXA₂ and PGF_2alpha  both produce vasoconstriction.  Additionally TXA₂, in the presence of testosterone, is mitogenic (increases cell proliferation).

PGI₂ and PGE₂ both produce vasodilatation.
 

GIT -- PGE₂ and PGF_2alpha  both produce contraction of intestinal longitudinal smooth muscle.  PGI₂ and PGF_2alpha  produce contraction of circular muscle, while PGE₂ relaxes circular muscle.  Additionally, in the intestinal tract, LTB₄ acts as a cytoattractant for neutrophils.  This has been clinically correlated with increases in LTB₄ in patients with inflammatory bowel disease.

Pulmonary SM -- PGE₁, PGE₂, and PGI₂ all relax bronchiolar smooth muscle while TXA₂, PGF_2alpha, LTC₄, and LTD₄ all cause bronchoconstriction.  Additionally, LTC₄ and LTD₄ will increase permeability and mucous secretion in the lung.
 

Blood Cells/Platelets -- PGE₁ and PGI₂ both decrease platelet aggregation while TXA₂ increases platelet aggregation, especially post-infarction.  LTB₄ acts as a neutrophil cytoattractant as well as modifying lymphocyte proliferation and differentiation.  LTC₄ and LTD₄ both cause eosinophil cytoattraction, adherence, degranulation, and subsequent oxygen radical formation.

Kidney -- The actions of the eicosanoids on the renal system are complex and not yet fully elucidated.  They may serve an autoregulatory purpose within the kidney.  PGE₂ and PGI₂ will increase renin release.  They also, along with PGE₁, will increase glomerular filtration (partially due to their vasodilatory actions) and decrease the effects of ADH, both of which will result in increased water and sodium loss.  It is currently hypothesised that loop diuretics work, at least in part, by increasing PG synthesis.  This hypothesis is supported by the decreased efficacy of furosemide when NSAIDs are administered concurrently.  TXA₂ increases water transport across tubular walls and may exhibit ADH like activity.
 

Reproductive System --
Female -- PGE₂ and PGF_2alpha  both produce oxytocic (uterine contractile) effects.  The sensitivity of the uterus to PG increases with term.  It is also hypothesised that dysmenorrhoea is at least partially due to the actions of PGs.

Male -- PGE₁ causes the relaxation of the smooth muscle of the corpora cavernosa, thereby aiding the erectile process.
 

Nervous System -- PGE₁ and PGE₂ both cause fever.  Their release is mediated by interleukin-1.  PGD₂ will induce sleep, however its role in the control over sleep patterns is unknown.  PGEs will decrease neurotransmitter release.  The role of this function is also unknown.

Endocrine System -- PGEs are assumed to play a role in regulating hormonal function since they will cause the release of TSH, GH, ACTH, FSH, LH, and Prolactin.

Bone -- Prostaglandins have some role in regulating bone growth.  Their presence will increase bone turnover.

Eye -- PGE and PGI will both decrease intraocular pressure.

Agonists
Dinoprostone -- PGE₂ -- This agent will induce labour and cause abortion.  It is used for both of these purposes (although it is unapproved for the induction of labour).  Note that often, abortions are incomplete if dinoprostone is the only abortifacient used, necessitating other means to accomplish complete abortion.  The dosage route is usually vaginal.  Side effects are primarily gastrointestinal disturbances and occur less frequently with the controlled release formulation (however, even in this preparation, the side effect incidence is greater than that seen with oxytocin).

Carboprost -- PGF_2alpha  -- This agent was used as an abortifacient.  A high incidence of cardiovascular collapse associated with the product caused its removal from the market.  It is not currently available in the United States of America.

Alprostadil -- PGE₁ -- This PG is used primarily in the treatment of male impotence due to erectile dysfunction.  It is available as either an injectable or urethral suppository.  Side effects include pain (up to 3%), priapism (4%), and fibrosis and penile angulation (up to 8%).  Another injectable formulation of alprostadil is used to maintain a patent ductus arteriosus prior to surgery.

Epoprostenol (prostacyclin) -- PGI₂ -- This agent is used primarily intravenously for the acute treatment of pulmonary hypertension.  Side effects include nausea, vomiting, headache, and flushing.

Misoprostol -- PGE₁ -- This PG is used for its cytoprotective effects on the gastric mucosa.  It is employed primarily as adjunctive therapy for patients with NSAID-induced gastric damage.  Side effects include abdominal pain and diarrhoea.

Latanoprost -- PGF_2alpha  -- Used topically to lower intraocular pressure in glaucoma.
 

Antagonists
Leukotriene Antagonists -- Zafirlukast, Montelukast -- These agents are non-selective, competitive antagonists for the LT receptor used primarily as adjunctive therapy in the treatment of asthma.  Montelukast may be taken without regard to food, however, zafirlukast should be taken on an empty stomach to enhance absorption.  Additionally, zafirlukast has been associated with liver dysfunction, increased blood levels of circulating theophylline and warfarin, and Churg-Strauss Syndrome of eosinophilic vasculitis.  The latter occurs especially if the patient suddenly discontinues the use of  glucocorticoid anti-inflammatory drugs.

Zileuton -- This agent inhibits the enzyme lipoxygenase, effectively inhibiting the synthesis of any of the LT family of eicosanoids.  It is used in the treatment of asthma.  As would be expected, it is not as specific as the leukotriene antagonist in its range of effects. Zileuton has also been associated with hepatotoxicity.

Cromolyn Sodium and Nedocromil -- These agents are used primarily for the prophylaxis of allergic or asthma attacks.  They inhibit the release of mediators (Histamine, LTs, PGs) from mast cells and eosinophils.  Mechanistically, they are thought to either alter chloride channels and/or inhibit intracellular calcium accumulation prior to degranulation and release of the mediator compounds.  This may not be their only mechanism since nedocromil is also effective (although less so) after degranulation has occurred.  Side effects following intranasal use include sneezing and nasal burning/stinging while oral cromolyn sodium (indicated for the treatment of mastocytosis) may produce nausea and/or diarrhoea.
 

Other, newer agents that possess mast cell stabilising activity include the following:
Pemirolast -- Ophthalmic -- Used to decrease "itchy" eyes associated with allergic rhinitis.  It has a relatively slow onset of action, taking days to work in some patients.

Lodoxamide -- Also Ophthalmic

Olopatadine and Ketotifien -- These agents are also used ophthalmically, but they also possess anti-histaminic activity in addition to the mast cell stabilisation activity.

 
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